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MitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress [yeast]

ABSTRACT: Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Physiological perturbations and disease conditions can lead to mitochondrial import defect. We find that in budding yeast, mitochondrial import defects result in activation of a surveillance mechanism, which we termed mitoCPR. The mitoCPR is aimed at ameliorating mitochondrial import and protecting mitochondria during import stress. This is mediated by the mitoCPR effector, Cis1, which associates with mitochondria to reduce the accumulation of mitochondrial preproteins at the organelle's surface. Clearance of preproteins depends on the AAA-ATPase Msp1 and the proteasome, suggesting that Cis1 facilitates the degradation of unimported proteins that accumulate at the mitochondrial surface. We further show that mitoCPR is critical for maintaining mitochondrial functions during mitochondrial import stress and provide evidence that it is an ancient, conserved mitochondrial protection mechanism.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE96727 | GEO | 2019/03/16

REPOSITORIES: GEO

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mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress

Project description:Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Various disease and stress conditions can lead to mitochondrial import defects. We find that inhibition of mitochondrial import in budding yeast activates a surveillance mechanism, mitoCPR, that is aimed at ameliorating mitochondrial import and protecting mitochondria during import stress. mitoCPR induces expression of Cis1 which associates with the mitochondrial translocase to reduce the accumulation of mitochondrial precursor proteins at the organelle surface. Clearance of precursor proteins depends on the Cis1 interacting AAA+ ATPase Msp1 and the proteasome suggesting that Cis1 facilitates degradation of un-imported proteins at the mitochondrial surface.

2018-04-20 | GSE107784 | GEO

mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress [human]

Project description:Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Physiological perturbations and disease conditions can lead to mitochondrial import defect. We find that in budding yeast, mitochondrial import defects result in activation of a surveillance mechanism, which we termed mitoCPR. The mitoCPR is aimed at ameliorating mitochondrial import and protecting mitochondria during import stress. This is mediated by the mitoCPR effector, Cis1, which associates with mitochondria to reduce the accumulation of mitochondrial preproteins at the organelle's surface. Clearance of preproteins depends on the AAA-ATPase Msp1 and the proteasome, suggesting that Cis1 facilitates the degradation of unimported proteins that accumulate at the mitochondrial surface. We further show that mitoCPR is critical for maintaining mitochondrial functions during mitochondrial import stress and provide evidence that it is an ancient, conserved mitochondrial protection mechanism.

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Mitochondrial protein import clogging as a mechanism of disease

Project description:Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in adenine nucleotide translocase 1 (Ant1), and its yeast homolog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of Ant1’s nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/Ant1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger Ant1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy Ant1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.

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mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress

Project description:mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress

| PRJNA379466 | ENA

mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress

Project description:mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress

| PRJNA421360 | ENA

Mitochondrial protein import stress augments alpha-synuclein aggregation and neurodegeneration independent of bioenergetics

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